Method and device for early signal attenuation detection using blood glucose measurements

ABSTRACT

Methods and devices to detect analyte in body fluid are provided. Embodiments include receiving one or more analyte sensor data, receiving a reference measurement value associated with an analyte level, determining a sensitivity parameter based on the received one or more analyte sensor data and the reference measurement value, performing a probability analysis based on prior analyte sensor data to determine presence of signal attenuation, and generating an output value based on the probability analysis.

BACKGROUND

The detection of the level of glucose or other analytes, such aslactate, oxygen or the like, in certain individuals is vitally importantto their health. For example, the monitoring of glucose is particularlyimportant to individuals with diabetes. Diabetics may need to monitorglucose levels to determine when insulin is needed to reduce glucoselevels in their bodies or when additional glucose is needed to raise thelevel of glucose in their bodies.

Devices have been developed for continuous or automatic monitoring ofanalytes, such as glucose, in bodily fluid such as in the blood streamor in interstitial fluid. Some of these analyte measuring devices areconfigured so that at least a portion of the devices are positionedbelow a skin surface of a user, e.g., in a blood vessel or in thesubcutaneous tissue of a user.

Following the sensor insertion, the resulting potential trauma to theskin and/or underlying tissue, for example, by the sensor introducerand/or the sensor itself, may, at times, result in instability ofsignals monitored by the sensor. This may occur in a number of analytesensors, but not in all cases. This instability is characterized by adecrease in the sensor signal, and when this occurs, generally, theanalyte levels monitored may not be reported, recorded or output to theuser.

SUMMARY

Embodiments of the subject disclosure include device and methods ofdetermining early signal attenuation (ESA) in signals from analytesensors. More specifically, embodiments include method, device andsystem for receiving one or more analyte sensor data, receiving areference measurement value associated with an analyte level,determining a sensitivity parameter based on the received one or moreanalyte sensor data and the reference measurement value, performing aprobability analysis based on prior analyte sensor data to determinepresence of signal attenuation, and generating an output value based onthe probability analysis.

Also provided are systems, computer program products, and kits.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a block diagram of an embodiment of a data monitoring andmanagement system according to the present disclosure;

FIG. 2 shows a block diagram of an embodiment of the transmitter unit ofthe data monitoring and management system of FIG. 1;

FIG. 3 shows a block diagram of an embodiment of the receiver/monitorunit of the data monitoring and management system of FIG. 1;

FIG. 4 shows a schematic diagram of an embodiment of an analyte sensoraccording to the present disclosure;

FIGS. 5A-5B show a perspective view and a cross sectional view,respectively of an embodiment the analyte sensor of FIG. 4;

FIG. 6 is a flowchart illustrating analyte sensor ESA conditiondetermination in accordance with one aspect of the present disclosure;

FIG. 7 is a flowchart illustrating probability of sensor signalattenuation determination of FIG. 6 in one aspect of the presentdisclosure;

FIG. 8 is a graph illustrating probability of ESA condition based onprior sensor data in accordance with one aspect of the presentdisclosure; and

FIG. 9 illustrates probability distribution functions of an analytesensor in ESA condition and when not in ESA condition based on sensorsensitivity in accordance with one aspect of the present disclosure.

DETAILED DESCRIPTION

Within the scope of the present disclosure, early signal attenuation(ESA) which may be attributable to associated instability of monitoredanalyte levels resulting from skin and/or tissue trauma when the sensoris transcutaneously positioned under the skin layer of a user may bedetermined using prior sensor data and analysis based upon the priordata.

Before the present disclosure is described in additional detail, it isto be understood that this disclosure is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present disclosure will be limited onlyby the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges is also encompassed within the disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present disclosure isnot entitled to antedate such publication by virtue of prior disclosure.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure.

The figures shown herein are not necessarily drawn to scale, with somecomponents and features being exaggerated for clarity.

Generally, embodiments of the present disclosure relate to methods anddevices for detecting at least one analyte such as glucose in bodyfluid. In certain embodiments, the present disclosure relates to thecontinuous and/or automatic in vivo monitoring of the level of ananalyte using an analyte sensor.

Accordingly, embodiments include analyte monitoring devices and systemsthat include an analyte sensor—at least a portion of which ispositionable beneath the skin of the user—for the in vivo detection, ofan analyte, such as glucose, lactate, and the like, in a body fluid.Embodiments include wholly implantable analyte sensors and analytesensors in which only a portion of the sensor is positioned under theskin and a portion of the sensor resides above the skin, e.g., forcontact to a transmitter, receiver, transceiver, processor, etc. Thesensor may be, for example, subcutaneously positionable in a patient forthe continuous or periodic monitoring of a level of an analyte in apatient's interstitial fluid. For the purposes of this description,continuous monitoring and periodic monitoring will be usedinterchangeably, unless noted otherwise. The analyte level may becorrelated and/or converted to analyte levels in blood or other fluids.In certain embodiments, an analyte sensor may be positioned in contactwith interstitial fluid to detect the level of glucose, which detectedglucose may be used to infer the glucose level in the patient'sbloodstream. Analyte sensors may be insertable into a vein, artery, orother portion of the body containing fluid. Embodiments of the analytesensors of the subject disclosure may be configured for monitoring thelevel of the analyte over a time period which may range from minutes,hours, days, weeks, or longer.

Of interest are analyte sensors, such as glucose sensors, that arecapable of in vivo detection of an analyte for about one hour or more,e.g., about a few hours or more, e.g., about a few days of more, e.g.,about three or more days, e.g., about five days or more, e.g., aboutseven days or more, e.g., about several weeks or at least one month.Future analyte levels may be predicted based on information obtained,e.g., the current analyte level at time to, the rate of change of theanalyte, etc. Predictive alarms may notify the user of predicted analytelevels that may be of concern prior in advance of the analyte levelreaching the future level. This enables the user an opportunity to takecorrective action.

FIG. 1 shows a data monitoring and management system such as, forexample, an analyte (e.g., glucose) monitoring system 100 in accordancewith certain embodiments. Embodiments of the subject disclosure arefurther described primarily with respect to glucose monitoring devicesand systems, and methods of glucose detection, for convenience only andsuch description is in no way intended to limit the scope of thedisclosure. It is to be understood that the analyte monitoring systemmay be configured to monitor a variety of analytes at the same time orat different times.

Analytes that may be monitored include, but are not limited to, acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin,creatine kinase (e.g., CK-MB), creatine, DNA, fructosamine, glucose,glutamine, growth hormones, hormones, ketones, lactate, peroxide,prostate-specific antigen, prothrombin, RNA, thyroid stimulatinghormone, and troponin. The concentration of drugs, such as, for example,antibiotics (e.g., gentamicin, vancomycin, and the like), digitoxin,digoxin, drugs of abuse, theophylline, and warfarin, may also bemonitored. In those embodiments that monitor more than one analyte, theanalytes may be monitored at the same or different times.

The analyte monitoring system 100 includes a sensor 101, a dataprocessing unit 102 connectable to the sensor 101, and a primaryreceiver unit 104 which is configured to communicate with the dataprocessing unit 102 via a communication link 103. In certainembodiments, the primary receiver unit 104 may be further configured totransmit data to a data processing terminal 105 to evaluate or otherwiseprocess or format data received by the primary receiver unit 104. Thedata processing terminal 105 may be configured to receive data directlyfrom the data processing unit 102 via a communication link which mayoptionally be configured for bi-directional communication. Further, thedata processing unit 102 may include a transmitter or a transceiver totransmit and/or receive data to and/or from the primary receiver unit104, the data processing terminal 105 or optionally the secondaryreceiver unit 106.

Also shown in FIG. 1 is an optional secondary receiver unit 106 which isoperatively coupled to the communication link and configured to receivedata transmitted from the data processing unit 102. The secondaryreceiver unit 106 may be configured to communicate with the primaryreceiver unit 104, as well as the data processing terminal 105. Thesecondary receiver unit 106 may be configured for bi-directionalwireless communication with each of the primary receiver unit 104 andthe data processing terminal 105. As discussed in further detail below,in certain embodiments the secondary receiver unit 106 may be ade-featured receiver as compared to the primary receiver, i.e., thesecondary receiver may include a limited or minimal number of functionsand features as compared with the primary receiver unit 104. As such,the secondary receiver unit 106 may include a smaller (in one or more,including all, dimensions), compact housing or embodied in a device suchas a wrist watch, arm band, etc., for example. Alternatively, thesecondary receiver unit 106 may be configured with the same orsubstantially similar functions and features as the primary receiverunit 104. The secondary receiver unit 106 may include a docking portionto be mated with a docking cradle unit for placement by, e.g., thebedside for night time monitoring, and/or bi-directional communicationdevice.

Only one sensor 101, data processing unit 102 and data processingterminal 105 are shown in the embodiment of the analyte monitoringsystem 100 illustrated in FIG. 1. However, it will be appreciated by oneof ordinary skill in the art that the analyte monitoring system 100 mayinclude more than one sensor 101 and/or more than one data processingunit 102, and/or more than one data processing terminal 105. Multiplesensors may be positioned in a patient for analyte monitoring at thesame or different times. In certain embodiments, analyte informationobtained by a first positioned sensor may be employed as a comparison toanalyte information obtained by a second sensor. This may be useful toconfirm or validate analyte information obtained from one or both of thesensors. Such redundancy may be useful if analyte information iscontemplated in critical therapy-related decisions. In certainembodiments, a first sensor may be used to calibrate a second sensor.

The analyte monitoring system 100 may be a continuous monitoring system,or semi-continuous, or a discrete monitoring system. In amulti-component environment, each component may be configured to beuniquely identified by one or more of the other components in the systemso that communication conflict may be readily resolved between thevarious components within the analyte monitoring system 100. Forexample, unique IDs, communication channels, and the like, may be used.

In certain embodiments, the sensor 101 is physically positioned in or onthe body of a user whose analyte level is being monitored. The sensor101 may be configured to at least periodically sample the analyte levelof the user and convert the sampled analyte level into a correspondingsignal for transmission by the data processing unit 102. The dataprocessing unit 102 is coupleable to the sensor 101 so that both devicesare positioned in or on the user's body, with at least a portion of theanalyte sensor 101 positioned transcutaneously. The data processing unit102 performs data processing functions, where such functions may includebut are not limited to, filtering and encoding of data signals, each ofwhich corresponds to a sampled analyte level of the user, fortransmission to the primary receiver unit 104 via the communication link103. In one embodiment, the sensor 101 or the data processing unit 102or a combined sensor/data processing unit may be wholly implantableunder the skin layer of the user.

In one aspect, the primary receiver unit 104 may include an analoginterface section including and RF receiver and an antenna that isconfigured to communicate with the data processing unit 102 via thecommunication link 103, data processing unit 102 and a data processingsection for processing the received data from the data processing unit102 such as data decoding, error detection and correction, data clockgeneration, and/or data bit recovery.

In operation, the primary receiver unit 104 in certain embodiments isconfigured to synchronize with the data processing unit 102 to uniquelyidentify the data processing unit 102, based on, for example, anidentification information of the data processing unit 102, andthereafter, to periodically receive signals transmitted from the dataprocessing unit 102 associated with the monitored analyte levelsdetected by the sensor 101.

Referring again to FIG. 1, the data processing terminal 105 may includea personal computer, a portable computer such as a laptop or a handhelddevice (e.g., personal digital assistants (PDAs), telephone such as acellular phone (e.g., a multimedia and Internet-enabled mobile phonesuch as an iPhone or similar phone), mp3 player, pager, and the like),drug delivery device, each of which may be configured for datacommunication with the receiver via a wired or a wireless connection.Additionally, the data processing terminal 105 may further be connectedto a data network (not shown) for storing, retrieving, updating, and/oranalyzing data corresponding to the detected analyte level of the user.

The data processing terminal 105 may include an infusion device such asan insulin infusion pump or the like, which may be configured toadminister insulin to patients, and which may be configured tocommunicate with the primary receiver unit 104 for receiving, amongothers, the measured analyte level. Alternatively, the primary receiverunit 104 may be configured to integrate an infusion device therein sothat the primary receiver unit 104 is configured to administer insulin(or other appropriate drug) therapy to patients, for example, foradministering and modifying basal profiles, as well as for determiningappropriate boluses for administration based on, among others, thedetected analyte levels received from the data processing unit 102. Aninfusion device may be an external device or an internal device (whollyimplantable in a user).

In particular embodiments, the data processing terminal 105, which mayinclude an insulin pump, may be configured to receive the analytesignals from the data processing unit 102, and thus, incorporate thefunctions of the primary receiver unit 104 including data processing formanaging the patient's insulin therapy and analyte monitoring. Incertain embodiments, the communication link 103 as well as one or moreof the other communication interfaces shown in FIG. 1 may use one ormore of an RF communication protocol, an infrared communicationprotocol, a Bluetooth enabled communication protocol, an 802.11xwireless communication protocol, or an equivalent wireless communicationprotocol which would allow secure, wireless communication of severalunits (for example, per HIPPA requirements) while avoiding potentialdata collision and interference.

FIG. 2 is a block diagram of the data processing unit of the datamonitoring and detection system shown in FIG. 1 in accordance withcertain embodiments. The data processing unit 102 thus may include oneor more of an analog interface 201 configured to communicate with thesensor 101 (FIG. 1), a user input 202, and a temperature detectionsection 203, each of which is operatively coupled to a transmitterprocessor 204 such as a central processing unit (CPU). The transmittermay include user input and/or interface components or may be free ofuser input and/or interface components.

Further shown in FIG. 2 are serial communication section 205 and an RFtransmitter 206, each of which is also operatively coupled to thetransmitter processor 204. Moreover, a power supply 207, such as abattery, may also be provided in the data processing unit 102 to providethe necessary power for the data processing unit 102. Additionally, ascan be seen from the Figure, clock 208 may be provided to, among others,supply real time information to the transmitter processor 204.

As can be seen in the embodiment of FIG. 2, the sensor unit 101 (FIG. 1)includes four contacts, three of which are electrodes—work electrode (W)210, guard contact (G) 211, reference electrode (R) 212, and counterelectrode (C) 213, each operatively coupled to the analog interface 201of the data processing unit 102. In certain embodiments, each of thework electrode (W) 210, guard contact (G) 211, reference electrode (R)212, and counter electrode (C) 213 may be made using a conductivematerial that may be applied by, e.g., chemical vapor deposition (CVD),physical vapor deposition, sputtering, reactive sputtering, printing,coating, ablating (e.g., laser ablation), painting, dip coating,etching, and the like. Materials include but are not limited toaluminum, carbon (such as graphite), cobalt, copper, gallium, gold,indium, iridium, iron, lead, magnesium, mercury (as an amalgam), nickel,niobium, osmium, palladium, platinum, rhenium, rhodium, selenium,silicon (e.g., doped polycrystalline silicon), silver, tantalum, tin,titanium, tungsten, uranium, vanadium, zinc, zirconium, mixturesthereof, and alloys, oxides, or metallic compounds of these elements.

The processor 204 may be configured to generate and/or process controlsignals to the various sections of the data processing unit 102 duringthe operation of the data processing unit 102. In certain embodiments,the processor 204 also includes memory (not shown) for storing data suchas the identification information for the data processing unit 102, aswell as the data associated with signals received from the sensor 101.The stored information may be retrieved and processed for transmissionto the primary receiver unit 104 under the control of the processor 204.Furthermore, the power supply 207 may include a commercially availablebattery.

In certain embodiments, a manufacturing process of the data processingunit 102 may place the data processing unit 102 in the lower power,non-operating state (i.e., post-manufacture sleep mode). In this manner,the shelf life of the data processing unit 102 may be significantlyimproved. Moreover, as shown in FIG. 2, while the power supply unit 207is shown as coupled to the processor 204, and as such, the processor 204is configured to provide control of the power supply unit 207, it shouldbe noted that within the scope of the present disclosure, the powersupply unit 207 is configured to provide the necessary power to each ofthe components of the data processing unit 102 shown in FIG. 2.

Referring back to FIG. 2, the power supply section 207 of the dataprocessing unit 102 in one embodiment may include a rechargeable batteryunit that may be recharged by a separate power supply recharging unit(for example, provided in the receiver unit 104) so that the dataprocessing unit 102 may be powered for a longer period of usage time. Incertain embodiments, the data processing unit 102 may be configuredwithout a battery in the power supply section 207, in which case thedata processing unit 102 may be configured to receive power from anexternal power supply source (for example, a battery, electrical outlet,etc.) as discussed in further detail below.

Referring yet again to FIG. 2, a temperature detection section 203 ofthe data processing unit 102 is configured to monitor the temperature ofthe skin near the sensor insertion site. The temperature reading may beused to adjust the analyte readings obtained from the analog interface201. Also shown is a leak detection circuit 214 coupled to the guardtrace (G) 211 and the processor 204 in the data processing unit 102 ofthe data monitoring and management system 100. The leak detectioncircuit 214 may be configured to detect leakage current in the sensor101 to determine whether the measured sensor data are corrupt or whetherthe measured data from the sensor 101 is accurate. Such detection maytrigger a notification to the user.

FIG. 3 is a block diagram of the receiver/monitor unit such as theprimary receiver unit 104 of the data monitoring and management systemshown in FIG. 1 in accordance with certain embodiments. The primaryreceiver unit 104 includes one or more of: a blood glucose test stripinterface 301, an RF receiver 302, an input 303, a temperature detectionsection 304, and a clock 305, each of which is operatively coupled to aprocessing and storage section 307. The primary receiver unit 104 alsoincludes a power supply 306 operatively coupled to a power conversionand monitoring section 308. Further, the power conversion and monitoringsection 308 is also coupled to the receiver processor 307. Moreover,also shown are a receiver serial communication section 309, and anoutput 310, each operatively coupled to the processing and storage unit307. The receiver may include user input and/or interface components ormay be free of user input and/or interface components.

In certain embodiments, the test strip interface 301 includes a glucoselevel testing portion to receive a blood (or other body fluid sample)glucose test or information related thereto. For example, the interfacemay include a test strip port to receive a glucose test strip. Thedevice may determine the glucose level of the test strip, and optionallydisplay (or otherwise notice) the glucose level on the output 310 of theprimary receiver unit 104. Any suitable test strip may be employed,e.g., test strips that only require a very small amount (e.g., onemicroliter or less, e.g., 0.5 microliter or less, e.g., 0.1 microliteror less), of applied sample to the strip in order to obtain accurateglucose information, e.g. FreeStyle® blood glucose test strips fromAbbott Diabetes Care, Inc. Glucose information obtained by the in vitroglucose testing device may be used for a variety of purposes,computations, etc. For example, the information may be used to calibratesensor 101, confirm results of the sensor 101 to increase the confidencethereof (e.g., in instances in which information obtained by sensor 101is employed in therapy related decisions), etc.

In one aspect, the RF receiver 302 is configured to communicate, via thecommunication link 103 (FIG. 1) with the RF transmitter 206 of the dataprocessing unit 102, to receive encoded data from the data processingunit 102 for, among others, signal mixing, demodulation, and other dataprocessing. The input 303 of the primary receiver unit 104 is configuredto allow the user to enter information into the primary receiver unit104 as needed. In one aspect, the input 303 may include keys of akeypad, a touch-sensitive screen, and/or a voice-activated input commandunit, and the like. The temperature monitor section 304 may beconfigured to provide temperature information of the primary receiverunit 104 to the processing and control section 307, while the clock 305provides, among others, real time or clock information to the processingand storage section 307.

Each of the various components of the primary receiver unit 104 shown inFIG. 3 is powered by the power supply 306 (or other power supply) which,in certain embodiments, includes a battery. Furthermore, the powerconversion and monitoring section 308 is configured to monitor the powerusage by the various components in the primary receiver unit 104 foreffective power management and may alert the user, for example, in theevent of power usage which renders the primary receiver unit 104 insub-optimal operating conditions. The serial communication section 309in the primary receiver unit 104 is configured to provide abi-directional communication path from the testing and/or manufacturingequipment for, among others, initialization, testing, and configurationof the primary receiver unit 104. Serial communication section 104 canalso be used to upload data to a computer, such as time-stamped bloodglucose data. The communication link with an external device (not shown)can be made, for example, by cable (such as USB or serial cable),infrared (IR) or RF link. The output/display 310 of the primary receiverunit 104 is configured to provide, among others, a graphical userinterface (GUI), and may include a liquid crystal display (LCD) fordisplaying information. Additionally, the output/display 310 may alsoinclude an integrated speaker for outputting audible signals as well asto provide vibration output as commonly found in handheld electronicdevices, such as mobile telephones, pagers, etc. In certain embodiments,the primary receiver unit 104 also includes an electro-luminescent lampconfigured to provide backlighting to the output 310 for output visualdisplay in dark ambient surroundings.

Referring back to FIG. 3, the primary receiver unit 104 may also includea storage section such as a programmable, non-volatile memory device aspart of the processor 307, or provided separately in the primaryreceiver unit 104, operatively coupled to the processor 307. Theprocessor 307 may be configured to perform Manchester decoding (or otherprotocol(s)) as well as error detection and correction upon the encodeddata received from the data processing unit 102 via the communicationlink 103.

In further embodiments, the data processing unit 102 and/or the primaryreceiver unit 104 and/or the secondary receiver unit 105, and/or thedata processing terminal/infusion section 105 may be configured toreceive the blood glucose value wirelessly over a communication linkfrom, for example, a blood glucose meter. In further embodiments, a usermanipulating or using the analyte monitoring system 100 (FIG. 1) maymanually input the blood glucose value using, for example, a userinterface (for example, a keyboard, keypad, voice commands, and thelike) incorporated in the one or more of the data processing unit 102,the primary receiver unit 104, secondary receiver unit 105, or the dataprocessing terminal/infusion section 105.

Additional detailed descriptions of embodiments of the continuousanalyte monitoring system, embodiments of its various components areprovided in U.S. Pat. No. 6,175,752 issued Jan. 16, 2001 entitled“Analyte Monitoring Device and Methods of Use”, and in application Ser.No. 10/745,878 filed Dec. 26, 2003 entitled “Continuous GlucoseMonitoring System and Methods of Use”, each assigned to the Assignee ofthe present application, and the disclosure of each of which areincorporated herein by reference for all purposes.

FIG. 4 schematically shows an embodiment of an analyte sensor inaccordance with the present disclosure. The sensor 400 includeselectrodes 401, 402 and 403 on a base 404. The sensor may be whollyimplantable in a user or may be configured so that only a portion ispositioned within (internal) a user and another portion outside(external) a user. For example, the sensor 400 may include a portionpositionable above a surface of the skin 410, and a portion positionedbelow the skin. In such embodiments, the external portion may includecontacts (connected to respective electrodes of the second portion bytraces) to connect to another device also external to the user such as atransmitter unit. While the embodiment of FIG. 4 shows three electrodesside-by-side on the same surface of base 404, other configurations arecontemplated, e.g., fewer or greater electrodes, some or all electrodeson different surfaces of the base or present on another base, some orall electrodes stacked together, electrodes of differing materials anddimensions, etc.

FIG. 5A shows a perspective view of an embodiment of an electrochemicalanalyte sensor 500 having a first portion (which in this embodiment maybe characterized as a major portion) positionable above a surface of theskin 510, and a second portion (which in this embodiment may becharacterized as a minor portion) that includes an insertion tip 530positionable below the skin, e.g., penetrating through the skin andinto, e.g., the subcutaneous space 520, in contact with the user'sbiofluid such as interstitial fluid. Contact portions of a workingelectrode 501, a reference electrode 502, and a counter electrode 503are positioned on the portion of the sensor 500 situated above the skinsurface 510. Working electrode 501, a reference electrode 502, and acounter electrode 503 are shown at the second section and particularlyat the insertion tip 530. Traces may be provided from the electrode atthe tip to the contact, as shown in FIG. 5A. It is to be understood thatgreater or fewer electrodes may be provided on a sensor. For example, asensor may include more than one working electrode and/or the counterand reference electrodes may be a single counter/reference electrode,etc.

FIG. 5B shows a cross sectional view of a portion of the sensor 500 ofFIG. 5A. The electrodes 510, 502 and 503, of the sensor 500 as well asthe substrate and the dielectric layers are provided in a layeredconfiguration or construction. For example, as shown in FIG. 5B, in oneaspect, the sensor 500 (such as the sensor unit 101 FIG. 1), includes asubstrate layer 504, and a first conducting layer 501 such as carbon,gold, etc., disposed on at least a portion of the substrate layer 504,and which may provide the working electrode. Also shown disposed on atleast a portion of the first conducting layer 501 is a sensing layer508.

Referring back to FIG. 5B, a first insulation layer such as a firstdielectric layer 505 is disposed or layered on at least a portion of thefirst conducting layer 501, and further, a second conducting layer 509may be disposed or stacked on top of at least a portion of the firstinsulation layer (or dielectric layer) 505. As shown in FIG. 5B, thesecond conducting layer 509 may provide the reference electrode 502, andin one aspect, may include a layer of silver/silver chloride (Ag/AgCl),gold, etc.

Referring still again to FIG. 5B, a second insulation layer 506 such asa dielectric layer in one embodiment may be disposed or layered on atleast a portion of the second conducting layer 509. Further, a thirdconducting layer 503 may provide the counter electrode 503. It may bedisposed on at least a portion of the second insulation layer 506.Finally, a third insulation layer may be disposed or layered on at leasta portion of the third conducting layer 503. In this manner, the sensor500 may be layered such that at least a portion of each of theconducting layers is separated by a respective insulation layer (forexample, a dielectric layer).

The embodiment of FIGS. 5A and 5B show the layers having differentlengths. Some or all of the layers may have the same or differentlengths and/or widths.

In certain embodiments, some or all of the electrodes 501, 502, 503 maybe provided on the same side of the substrate 504 in the layeredconstruction as described above, or alternatively, may be provided in aco-planar manner such that two or more electrodes may be positioned onthe same plane (e.g., side-by side (e.g., parallel) or angled relativeto each other) on the substrate 504. For example, co-planar electrodesmay include a suitable spacing there between and/or include dielectricmaterial or insulation material disposed between the conductinglayers/electrodes. Furthermore, in certain embodiments one or more ofthe electrodes 501, 502, 503 may be disposed on opposing sides of thesubstrate 504. In such embodiments, contact pads may be one the same ordifferent sides of the substrate. For example, an electrode may be on afirst side and its respective contact may be on a second side, e.g., atrace connecting the electrode and the contact may traverse through thesubstrate.

In certain embodiments, the data processing unit 102 may be configuredto perform sensor insertion detection and data quality analysis,information pertaining to which may also transmitted to the primaryreceiver unit 104 periodically at the predetermined time interval. Inturn, the receiver unit 104 may be configured to perform, for example,skin temperature compensation/correction as well as calibration of thesensor data received from the data processing unit 102.

As noted above, analyte sensors may include an analyte-responsive enzymein a sensing layer. Some analytes, such as oxygen, can be directlyelectrooxidized or electroreduced on a sensor, and more specifically atleast on a working electrode of a sensor. Other analytes, such asglucose and lactate, require the presence of at least one electrontransfer agent and/or at least one catalyst to facilitate theelectrooxidation or electroreduction of the analyte. Catalysts may alsobe used for those analyte, such as oxygen, that can be directlyelectrooxidized or electroreduced on the working electrode. For theseanalytes, each working electrode includes a sensing layer (see forexample sensing layer 508 of FIG. 5B) formed proximate to or on asurface of a working electrode. In many embodiments, a sensing layer isformed near or on only a small portion of at least a working electrode.

A variety of different sensing layer configurations may be used. Incertain embodiments, the sensing layer is deposited on the conductivematerial of a working electrode. The sensing layer may extend beyond theconductive material of the working electrode. In some cases, the sensinglayer may also extend over other electrodes, e.g., over the counterelectrode and/or reference electrode (or counter/reference is provided).The sensing layer may be integral with the material of an electrode.

A sensing layer that is in direct contact with the working electrode maycontain an electron transfer agent to transfer electrons directly orindirectly between the analyte and the working electrode, and/or acatalyst to facilitate a reaction of the analyte.

A sensing layer that is not in direct contact with the working electrodemay include a catalyst that facilitates a reaction of the analyte.However, such sensing layers may not include an electron transfer agentthat transfers electrons directly from the working electrode to theanalyte, as the sensing layer is spaced apart from the workingelectrode. One example of this type of sensor is a glucose or lactatesensor which includes an enzyme (e.g., glucose oxidase, glucosedehydrogenase, lactate oxidase, and the like) in the sensing layer. Theglucose or lactate may react with a second compound in the presence ofthe enzyme. The second compound may then be electrooxidized orelectroreduced at the electrode. Changes in the signal at the electrodeindicate changes in the level of the second compound in the fluid andare proportional to changes in glucose or lactate level and, thus,correlate to the analyte level.

In certain embodiments which include more than one working electrode,one or more of the working electrodes do not have a correspondingsensing layer, or have a sensing layer which does not contain one ormore components (e.g., an electron transfer agent and/or catalyst)needed to electrolyze the analyte. Thus, the signal at this workingelectrode corresponds to background signal which may be removed from theanalyte signal obtained from one or more other working electrodes thatare associated with fully-functional sensing layers by, for example,subtracting the signal.

In certain embodiments, the sensing layer includes one or more electrontransfer agents. Electron transfer agents that may be employed areelectroreducible and electrooxidizable ions or molecules having redoxpotentials that are a few hundred millivolts above or below the redoxpotential of the standard calomel electrode (SCE). The electron transferagent may be organic, organometallic, or inorganic.

In certain embodiments, electron transfer agents have structures orcharges which prevent or substantially reduce the diffusional loss ofthe electron transfer agent during the period of time that the sample isbeing analyzed. For example, electron transfer agents include but arenot limited to a redox species, e.g., bound to a polymer which can inturn be disposed on or near the working electrode. The bond between theredox species and the polymer may be covalent, coordinative, or ionic.Although any organic or organometallic redox species may be bound to apolymer and used as an electron transfer agent, in certain embodimentsthe redox species is a transition metal compound or complex, e.g.,osmium, ruthenium, iron, and cobalt compounds or complexes. It will berecognized that many redox species described for use with a polymericcomponent may also be used, without a polymeric component.

One type of polymeric electron transfer agent contains a redox speciescovalently bound in a polymeric composition. An example of this type ofmediator is poly(vinylferrocene). Another type of electron transferagent contains an ionically-bound redox species. This type of mediatormay include a charged polymer coupled to an oppositely charged redoxspecies. Examples of this type of mediator include a negatively chargedpolymer coupled to a positively charged redox species such as an osmiumor ruthenium polypyridyl cation. Another example of an ionically-boundmediator is a positively charged polymer such as quaternizedpoly(4-vinyl pyridine) or poly(1-vinyl imidazole) coupled to anegatively charged redox species such as ferricyanide or ferrocyanide.In other embodiments, electron transfer agents include a redox speciescoordinatively bound to a polymer. For example, the mediator may beformed by coordination of an osmium or cobalt 2,2′-bipyridyl complex topoly(1-vinyl imidazole) or poly(4-vinyl pyridine).

Suitable electron transfer agents are osmium transition metal complexeswith one or more ligands, each ligand having a nitrogen-containingheterocycle such as 2,2′-bipyridine, 1,10-phenanthroline, or derivativesthereof. The electron transfer agents may also have one or more ligandscovalently bound in a polymer, each ligand having at least onenitrogen-containing heterocycle, such as pyridine, imidazole, orderivatives thereof. The present disclosure may employ electron transferagents have a redox potential ranging from about −100 mV to about +150mV versus the standard calomel electrode (SCE), e.g., ranges from about−100 mV to about +150 mV, e.g., ranges from about −50 mV to about +50mV, e.g., electron transfer agents have osmium redox centers and a redoxpotential ranging from +50 mV to −150 mV versus SCE.

The sensing layer may also include a catalyst which is capable ofcatalyzing a reaction of the analyte. The catalyst may also, in someembodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, such as a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone glucose dehydrogenase(PQQ)), or oligosaccharide dehydrogenase), may be used when the analyteof interest is glucose. A lactate oxidase or lactate dehydrogenase maybe used when the analyte of interest is lactate. Laccase may be usedwhen the analyte of interest is oxygen or when oxygen is generated orconsumed in response to a reaction of the analyte. In certainembodiments, a catalyst may be attached to a polymer, cross linking thecatalyst with another electron transfer agent (which, as describedabove, may be polymeric. A second catalyst may also be used in certainembodiments. This second catalyst may be used to catalyze a reaction ofa product compound resulting from the catalyzed reaction of the analyte.The second catalyst may operate with an electron transfer agent toelectrolyze the product compound to generate a signal at the workingelectrode. Alternatively, a second catalyst may be provided in aninterferent-eliminating layer to catalyze reactions that removeinterferents.

Certain embodiments include a Wired Enzyme™ sensing layer that works ata gentle oxidizing potential, e.g., a potential of about +40 mV. Thissensing layer uses an osmium (Os)-based mediator designed for lowpotential operation and is stably anchored in a polymeric layer.Accordingly, in certain embodiments the sensing element is redox activecomponent that includes (1) Osmium-based mediator molecules attached bystable (bidente) ligands anchored to a polymeric backbone, and (2)glucose oxidase enzyme molecules. These two constituents are crosslinkedtogether.

A mass transport limiting layer (not shown), e.g., an analyte fluxmodulating layer, may be included with the sensor to act as adiffusion-limiting barrier to reduce the rate of mass transport of theanalyte, for example, glucose or lactate, into the region around theworking electrodes. The mass transport limiting layers are useful inlimiting the flux of an analyte to a working electrode in anelectrochemical sensor so that the sensor is linearly responsive over alarge range of analyte concentrations and is easily calibrated. Masstransport limiting layers may include polymers and may be biocompatible.A mass transport limiting layer may serve many functions, e.g.,functionalities of a biocompatible layer and/or interferent-eliminatinglayer may be provided by the mass transport limiting layer.

In certain embodiments, a mass transport limiting layer is a membranecomposed of crosslinked polymers containing heterocyclic nitrogengroups, such as polymers of polyvinylpyridine and polyvinylimidazole.Electrochemical sensors equipped with such membranes have considerablesensitivity and stability, and a large signal-to-noise ratio, in avariety of conditions.

According certain embodiments, a membrane is formed by crosslinking insitu a polymer, modified with a zwitterionic moiety, a non-pyridinecopolymer component, and optionally another moiety that is eitherhydrophilic or hydrophobic, and/or has other desirable properties, in analcohol-buffer solution. The modified polymer may be made from aprecursor polymer containing heterocyclic nitrogen groups. Optionally,hydrophilic or hydrophobic modifiers may be used to “fine-tune” thepermeability of the resulting membrane to an analyte of interest.Optional hydrophilic modifiers, such as poly(ethylene glycol), hydroxylor polyhydroxyl modifiers, may be used to enhance the biocompatibilityof the polymer or the resulting membrane.

A biocompatible layer (not shown) may be provided over at least thatportion of the sensor which is subcutaneously inserted into the patient.The biocompatible layer may be incorporated in theinterferent-eliminating layer or in the mass transport limiting layer ormay be a separate layer. The layer may prevent the penetration of largebiomolecules into the electrodes. The biocompatible layer may alsoprevent protein adhesion to the sensor, formation of blood clots, andother undesirable interactions between the sensor and body. For example,a sensor may be completely or partially covered on its exterior with abiocompatible coating.

An interferent-eliminating layer (not shown) may be included in thesensor. The interferent-eliminating layer may be incorporated in thebiocompatible layer or in the mass transport limiting layer or may be aseparate layer. Interferents are molecules or other species that areelectroreduced or electrooxidized at the electrode, either directly orvia an electron transfer agent, to produce a false signal. In oneembodiment, a film or membrane prevents the penetration of one or moreinterferents into the region around the working electrode. In manyembodiments, this type of interferent-eliminating layer is much lesspermeable to one or more of the interferents than to the analyte. Aninterferent-eliminating layer may include ionic components to reduce thepermeability of the interferent-eliminating layer to ionic interferentshaving the same charge as the ionic components. Another example of aninterferent-eliminating layer includes a catalyst for catalyzing areaction which removes interferents.

A sensor may also include an active agent such as an anticlotting and/orantiglycolytic agent(s) disposed on at least a portion a sensor that ispositioned in a user. An anticlotting agent may reduce or eliminate theclotting of blood or other body fluid around the sensor, particularlyafter insertion of the sensor. Blood clots may foul the sensor orirreproducibly reduce the amount of analyte which diffuses into thesensor. Examples of useful anticlotting agents include heparin andtissue plasminogen activator (TPA), as well as other known anticlottingagents. Embodiments may include an antiglycolytic agent or precursorthereof. The term “antiglycolytic” is used broadly herein to include anysubstance that at least retards glucose consumption of living cells.

Sensors described herein may be configured to require no systemcalibration or no user calibration. For example, a sensor may be factorycalibrated and need not require further calibrating. In certainembodiments, calibration may be required, but may be done without userintervention, i.e., may be automatic. In those embodiments in whichcalibration by the user is required, the calibration may be according toa predetermined schedule or may be dynamic, i.e., the time for which maybe determined by the system on a real-time basis according to variousfactors. Calibration may be accomplished using an in vitro test strip orother calibrator, e.g., a small sample test strip such as a test stripthat requires less than about 1 microliter of sample (for exampleFreeStyle® blood glucose monitoring test strips from Abbott DiabetesCare, Inc). For example, test strips that require less than about 1nanoliter of sample may be used. In certain embodiments, a sensor may becalibrated using only one sample of body fluid per calibration event.For example, a user using need only lance a body part one time to obtainsample for a calibration event (e.g., for a test strip), or may lancemore than one time within a short period of time if an insufficientvolume of sample is obtained firstly. Embodiments include obtaining andusing multiple samples of body fluid for a given calibration event,where glucose values of each sample are substantially similar. Dataobtained from a given calibration event may be used independently tocalibrate or combined with data obtained from previous calibrationevents, e.g., averaged including weighted averaged, filtered and thelike, to calibrate.

An analyte system may include an optional alarm system that, e.g., basedon information from a processor, warns the patient of a potentiallydetrimental condition of the analyte. For example, if glucose is theanalyte, an alarm system may warn a user of conditions such ashypoglycemia and/or hyperglycemia and/or impending hypoglycemia, and/orimpending hyperglycemia. An alarm system may be triggered when analytelevels reach or exceed a threshold value. An alarm system may also, oralternatively, be activated when the rate of change or acceleration ofthe rate of change in analyte level increase or decrease reaches orexceeds a threshold rate or acceleration. For example, in the case of aglucose monitoring system, an alarm system may be activated if the rateof change in glucose concentration exceeds a threshold value which mightindicate that a hyperglycemic or hypoglycemic condition is likely tooccur. A system may also include system alarms that notify a user ofsystem information such as battery condition, calibration, sensordislodgment, sensor malfunction, etc. Alarms may be, for example,auditory and/or visual. Other sensory-stimulating alarm systems may beused including alarm systems which heat, cool, vibrate, or produce amild electrical shock when activated.

The subject disclosure also includes sensors used in sensor-based drugdelivery systems. The system may provide a drug to counteract the highor low level of the analyte in response to the signals from one or moresensors. Alternatively, the system may monitor the drug concentration toensure that the drug remains within a desired therapeutic range. Thedrug delivery system may include one or more (e.g., two or more)sensors, a transmitter, a receiver/display unit, and a drugadministration system. In some cases, some or all components may beintegrated in a single unit. The sensor-based drug delivery system mayuse data from the one or more sensors to provide necessary input for acontrol algorithm/mechanism to adjust the administration of drugs, e.g.,automatically or semi-automatically. As an example, a glucose sensorcould be used to control and adjust the administration of insulin froman external or implanted insulin pump.

Referring again to the Figures, the probability determination of whetheran analyte sensor is in ESA condition in accordance with one aspect ofthe present disclosure is described in further detail. Morespecifically, FIG. 6 is a flowchart illustrating analyte sensor ESAcondition determination in accordance with one aspect of the presentdisclosure. Referring to the Figure, one or more signals related to theanalyte level monitored is received from the analyte sensor (610). Areference measurement value is also received (620). For example, thereference measurement value may include the result of acontemporaneously performed blood glucose test using an in vitro bloodglucose meter. With the analyte data and the time correspondingreference measurement value, the sensor sensitivity is determined, forexample, by determining the ratio of the analyte data and the referencemeasurement value (630).

Referring back to FIG. 6, the probability of analyte sensor ESAcondition is determined based on prior sensor data analysis (640) asdiscussed in further detail below in conjunction with FIG. 7, andthereafter, the determination of whether the analyte sensor is in ESAcondition or not based on the determined probability of sensor signalattenuation is generated (650). In one aspect, as discussed in furtherdetail below, the determination of the probability of sensor ESAcondition may be based at least in part on a probability analysis of thesensor data based on previously collected and/or received sensor data(whether from the same or different sensor), and/or based at least inpart on the probability of the ESA condition based on the determinedsensor sensitivity in view of the probability analysis performed on thepreviously monitored and/or stored analyte data and associatedparameters such as sensor sensitivity.

Referring now to FIG. 7 which is a flowchart illustrating probability ofsensor signal attenuation determination of FIG. 6, in one aspect, acurrent sensor data parameter is compared to prior probability of ESAfunction (710). For example, with reference to FIG. 8 which illustratesa graph illustrating probability of ESA condition based on historicalsensor data, and without any data from the present sensor, it can beseen that the prior probability of being in the ESA condition peaks atapproximately 0.28 at 4.5 hours, for example, from sensor insertion orpositioning in fluid contact with an analyte. In one aspect, theprobability of ESA condition based on past analyte data may be stored ina lookup table in one or more data storage units or memory device in thereceiver unit (104/106) (FIG. 1), or in a computer terminal or a remotedevice that has stored therein the prior sensor data information.

Referring back to FIG. 7, it is also determined, based on the analytesensor sensitivity determined (FIG. 6), the likelihood of the ESAcondition based on the determined sensitivity, for example, by comparingwith probability distribution functions (PDFs) which illustrate howlikely a sensor with a given sensitivity value is in ESA, or is not inESA (720). These probability distribution functions may be also derivedfrom historical sensor data, but are used in this analysis only afterthere is data from the present sensor. More specifically, by way of anon-limiting example, FIG. 9 shows the “not in ESA” sensitivityprobability distribution function (PDF) with a peak value ofapproximately 2, and the “in ESA” sensitivity probability distributionfunction (PDF) peak at a smaller value of sensitivity, attaining a valueof approximately 1.75.

Referring still again to FIG. 7, the prior probability value (from FIG.8 or a similar curve), and the likelihood values of being in ESA and ofnot being in ESA (from FIG. 9 or similar curves), are combined using apredefined rule or relationship, such as based on, for example, BayesLaw (730).

Referring yet still to FIG. 7, with the ESA condition determination(730), the ESA condition determination value is reported (740), and maybe compared to a predetermined threshold to conclude or ascertainwhether or not the analyte sensor is in ESA condition. For example, inone aspect, the predetermined threshold value may be programmed orconfigured to be a set value to which is compared the output result ofthe ESA condition determination value. In the event that the comparisonyields the ESA condition determination value exceeding the predeterminedthreshold value, then the analyte monitoring system 100 (FIG. 1) may beconfigured (for example, by the receiver unit (104/106)) to confirm thepresence of ESA condition for the analyte sensor.

In accordance with embodiments of the present disclosure, thepredetermined threshold value may be varied, based at least in part, onthe prior analysis of the past sensor data stored and processed, forexample, in the receiver unit (104/106). Alternatively, depending uponthe sensor parameters (for example, nominal sensor code, manufacturingprocess, sensing chemistry, and the like), there may be associatedtherewith a predefined or preset threshold value which may be used tocompare and determine whether ESA condition is present.

In this manner, in accordance with embodiments of the presentdisclosure, analyte sensor early signal attenuation condition may bedetermined, retrospectively or in real time, based, at least in part ananalysis of the past sensor data over a predetermined time period (forexample, 30 days or 50 days), and with sensitivity values available forthe sensors, a probability function may be used to determine thepresence of ESA condition, for example.

When ESA condition is not determined and/or the sensor reaches theequilibration level within the short time period, then the analytemonitoring system may be configured to request a reference measurementvalue (e.g., blood glucose value) from the user, for example, afingerstick in vitro test using a blood glucose meter, to calibrate thesensor signals, and thereafter, report or display to the user themonitored analyte levels. Upon successful calibration, the resultingcalibrated analyte levels may be displayed to the user, or otherwisestored or logged in the analyte monitoring system or device and/ortransmitted to a remote device or computing terminal for furtherprocessing.

When the ESA condition is determined based upon, in part, theprobability function described herein, for example, the analytemonitoring system may be configured to alert the user to wait apredetermined time period before providing the reference blood glucosevalue to provide the sensor to stabilize, or alternatively, the user maybe prompted to provide the reference blood glucose value to confirm thepresence of the ESA condition.

In one aspect, the scheduled calibration of the analyte sensor may bedelayed to provide the sensor additional time period to reach a desiredor acceptable stability level. Among other conditions, boundaries may beestablished to provide the sensor additional time period to reach apredetermined or acceptable stability level before the received analytesensor signals are calibrated, and thus, provided to the user. In thismanner, in one aspect, when it is determined that the transcutaneouslypositioned sensor has reached an acceptable stability level resulting inthe desired or predetermined equilibration level, the analyte monitoringsystem may display or otherwise accept, output, log, or process themonitored analyte level, substantially in real time, received from thetranscutaneously positioned sensor.

In the case where ESA condition or the potential for such signalattenuation is determined, the analyte monitoring system may beconfigured in one embodiment to perform one or more routines orfunctions to verify the sensor related signals to confirm the ESAcondition, to notify the user to refrain from performing a fingersticktest using a blood glucose meter to provide a reference blood glucosevalue for calibration, among others.

Accordingly, in one aspect, a method includes receiving one or moreanalyte sensor data, receiving a reference measurement value associatedwith an analyte level, determining a sensitivity parameter based on thereceived one or more analyte sensor data and the reference measurementvalue, performing a probability analysis based on prior analyte sensordata to determine presence of signal attenuation, and generating anoutput value based on the probability analysis.

In one embodiment, performing a probability analysis may includedetermining a sensor signal attenuation profile based on the prioranalyte sensor data, where the sensor signal attenuation profile mayinclude a value determined at least in part by a sensor calibrationschedule.

The prior analyte sensor data may include data associated with monitoredanalyte level over a predetermined time period, including approximately30 days, 50 days, 100 days, or any other suitable time periods fromwhich a basis for data analysis may be performed.

In still another aspect, performing a probability analysis may includedetermining the presence or the absence of signal attenuation based atleast in part on the sensitivity parameter, where the determination mayinclude retrieving one or more parameters associated with signalattenuation associated with the sensitivity parameter.

Another aspect may also include comparing the output value to apredetermined threshold level.

A further may additionally include determining the presence of signalattenuation condition for the analyte sensor based on the comparison,where the predetermined threshold level may be adjustable or modifiableby the system and/or the user.

In still another aspect, performing the probability analysis may includeapplying a predetermined probability function to the sensitivityparameter.

Further, calibrating the received one or more analyte sensor data basedat least in part on the determined sensitivity parameter may beincluded, and also, displaying the calibrated one or more analyte sensordata to a suitable output device such as a visual display, an auditoryoutput and/or a vibratory or tactile output device or component.

An apparatus in another aspect of the present disclosure includes a datacommunication interface, one or more processors operatively coupled tothe data communication interface, and a memory for storing instructionswhich, when executed by the one or more processors, causes the one ormore processors to receive one or more analyte sensor data, receive areference measurement value associated with an analyte level, determinea sensitivity parameter based on the received one or more analyte sensordata and the reference measurement value, perform a probability analysisbased on prior analyte sensor data to determine presence of signalattenuation, and generate an output value based on the probabilityanalysis.

The memory for storing instructions which, when executed by the one ormore processors, may cause the one or more processors to determine asensor signal attenuation profile based on the prior analyte sensordata, where the sensor signal attenuation profile may include a valuedetermined at least in part by a sensor calibration schedule.

In another aspect, the memory for storing instructions which, whenexecuted by the one or more processors, may cause the one or moreprocessors to determine the presence or the absence of signalattenuation based at least in part on the sensitivity parameter, also,where the memory for storing instructions which, when executed by theone or more processors, may cause the one or more processors to retrieveone or more parameters associated with signal attenuation associatedwith the sensitivity parameter.

In still another aspect, the memory for storing instructions which, whenexecuted by the one or more processors, may cause the one or moreprocessors to compare the output value to a predetermined thresholdlevel.

Further, the memory for storing instructions which, when executed by theone or more processors, may cause the one or more processors todetermine the presence of signal attenuation condition for the analytesensor based on the comparison, where the predetermined threshold levelmay be adjustable.

In yet still a further aspect, the memory for storing instructionswhich, when executed by the one or more processors, may cause the one ormore processors to apply a predetermined probability function to thesensitivity parameter.

Moreover, the memory for storing instructions which, when executed bythe one or more processors, may cause the one or more processors tocalibrate the received one or more analyte sensor data based at least inpart on the determined sensitivity parameter.

Also, the apparatus may include an output unit operatively coupled tothe one or more processors, where the memory for storing instructionswhich, when executed by the one or more processors, may cause the one ormore processors to output the calibrated one or more analyte sensordata.

In yet a further aspect of the present disclosure, there is provided oneor more storage devices having processor readable code embodied thereon,said processor readable code for programming one or more processors todetermine signal attenuation condition including receiving one or moreanalyte sensor data, receiving a reference measurement value associatedwith an analyte level, determining a sensitivity parameter based on thereceived one or more analyte sensor data and the reference measurementvalue, performing a probability analysis based on prior analyte sensordata to determine presence of signal attenuation, and generating anoutput value based on the probability analysis.

The various processes described above including the processes performedby the data processing unit 102, receiver unit 104/106 or the dataprocessing terminal/infusion section 105 (FIG. 1) in the softwareapplication execution environment in the analyte monitoring system 100including the processes and routines described in conjunction with FIGS.6-7, may be embodied as computer programs developed using an objectoriented language that allows the modeling of complex systems withmodular objects to create abstractions that are representative of realworld, physical objects and their interrelationships. The softwarerequired to carry out the inventive process, which may be stored in thememory or storage device (not shown) of the data processing unit 102,receiver unit 104/106 or the data processing terminal/infusion section105, may be developed by a person of ordinary skill in the art and mayinclude one or more computer program products.

Various other modifications and alterations in the structure and methodof operation of this disclosure will be apparent to those skilled in theart without departing from the scope and spirit of the embodiments ofthe present disclosure. Although the present disclosure has beendescribed in connection with particular embodiments, it should beunderstood that the present disclosure as claimed should not be undulylimited to such particular embodiments. It is intended that thefollowing claims define the scope of the present disclosure and thatstructures and methods within the scope of these claims and theirequivalents be covered thereby.

1. A method, comprising: receiving one or more analyte sensor data froman analyte sensor in fluid contact with interstitial fluid under a skinlayer; receiving a reference measurement value associated with ananalyte level; determining a sensitivity parameter based on the receivedone or more analyte sensor data and the reference measurement value;performing a probability analysis based on prior analyte sensor data todetermine presence of signal attenuation, the probability analysisincluding comparing the determined sensitivity parameter to aprobability distribution function that provides a likelihood of theanalyte sensor with the determined sensitivity parameter in signalattenuation condition; and generating an output value based on theprobability analysis.
 2. The method of claim 1 wherein performing theprobability analysis includes determining a sensor signal attenuationprofile based on the prior analyte sensor data.
 3. The method of claim 2wherein the sensor signal attenuation profile includes a valuedetermined at least in part by a sensor calibration schedule.
 4. Themethod of claim 1 wherein the prior analyte sensor data includes dataassociated with monitored analyte level over a predetermined timeperiod.
 5. The method of claim 1 wherein performing a probabilityanalysis includes determining the presence or the absence of signalattenuation based at least in part on the sensitivity parameter.
 6. Themethod of claim 5 wherein the determining includes retrieving one ormore parameters associated with signal attenuation associated with thesensitivity parameter.
 7. The method of claim 1 including comparing theoutput value to a predetermined threshold level.
 8. The method of claim7 including determining the presence of signal attenuation condition forthe analyte sensor based on the comparison.
 9. The method of claim 7wherein the predetermined threshold level is adjustable.
 10. The methodof claim 1 wherein performing the probability analysis includes applyinga predetermined probability function to the sensitivity parameter. 11.The method of claim 1 including calibrating the received one or moreanalyte sensor data based at least in part on the determined sensitivityparameter.
 12. The method of claim 11 including displaying thecalibrated one or more analyte sensor data.
 13. An apparatus,comprising: a data communication interface; one or more processorsoperatively coupled to the data communication interface; and a memoryfor storing instructions which, when executed by the one or moreprocessors, causes the one or more processors to receive one or moreanalyte sensor data from an analyte sensor in fluid contact withinterstitial fluid under a skin layer, receive a reference measurementvalue associated with an analyte level, determine a sensitivityparameter based on the received one or more analyte sensor data and thereference measurement value, perform a probability analysis based onprior analyte sensor data to determine presence of signal attenuation,the probability analysis including comparison of the determinedsensitivity parameter to a probability distribution function thatprovides a likelihood of the analyte sensor with the determinedsensitivity parameter in signal attenuation condition, and generate anoutput value based on the probability analysis.
 14. The apparatus ofclaim 13 wherein the memory for storing instructions which, whenexecuted by the one or more processors, causes the one or moreprocessors to determine a sensor signal attenuation profile based on theprior analyte sensor data.
 15. The apparatus of claim 14 wherein thesensor signal attenuation profile includes a value determined at leastin part by a sensor calibration schedule.
 16. The apparatus of claim 13wherein the memory for storing instructions which, when executed by theone or more processors, causes the one or more processors to determinethe presence or the absence of signal attenuation based at least in parton the sensitivity parameter.
 17. The apparatus of claim 16 wherein thememory for storing instructions which, when executed by the one or moreprocessors, causes the one or more processors to retrieve one or moreparameters associated with signal attenuation associated with thesensitivity parameter.
 18. The apparatus of claim 17 wherein the memoryfor storing instructions which, when executed by the one or moreprocessors, causes the one or more processors to compare the outputvalue to a predetermined threshold level.
 19. The apparatus of claim 18wherein the memory for storing instructions which, when executed by theone or more processors, causes the one or more processors to determinethe presence of signal attenuation condition for the analyte sensorbased on the comparison.
 20. The apparatus of claim 18 wherein thepredetermined threshold level is adjustable.
 21. The apparatus of claim13 wherein the memory for storing instructions which, when executed bythe one or more processors, causes the one or more processors to apply apredetermined probability function to the sensitivity parameter.
 22. Theapparatus of claim 13 wherein the memory for storing instructions which,when executed by the one or more processors, causes the one or moreprocessors to calibrate the received one or more analyte sensor databased at least in part on the determined sensitivity parameter.
 23. Theapparatus of claim 13 including an output unit operatively coupled tothe one or more processors, wherein the memory for storing instructionswhich, when executed by the one or more processors, causes the one ormore processors to output the calibrated one or more analyte sensordata.
 24. One or more storage devices having processor readable codeembodied thereon, said processor readable code for programming one ormore processors to identify presence of signal attenuation condition,comprising: receiving one or more analyte sensor data from an analytesensor in fluid contact with interstitial fluid under a skin layer;receiving a reference measurement value associated with an analytelevel; determining a sensitivity parameter based on the received one ormore analyte sensor data and the reference measurement value; performinga probability analysis based on prior analyte sensor data to determinepresence of signal attenuation, the probability analysis includingcomparing the determined sensitivity parameter to a probabilitydistribution function that provides a likelihood of the analyte sensorwith the determined sensitivity parameter in signal attenuationcondition; and generating an output value based on the probabilityanalysis.